Regeneration medicine has attracted attention as medical treatment for the purpose of regenerating a cell, tissue or organ lost due to a disease or accident; or of recovering the function thereof. Regeneration medicine also includes cell transplantation using living cells, such as skin transplantation and organ transplantation, and particularly in recent years, the technology of differentiating stem cells into cells having the function of each tissue thereby regenerating an organ or tissue which is not capable of spontaneous regeneration or recovering the function thereof has been developed, and generation medicine utilizing this technology attract attention.
Stem cells are juvenile, undifferentiated parent cells having self-regenerating ability as a source growing into a tissue or organ for replenishing cells approaching death. Embryonic stem cells (ES cells) derived from embryos attract attention, but cannot become autologous cells without nuclear transfer to somatic cells, thus causing immunological rejection upon transplantation and requiring necessity for genetic recombination, confirmation of HLA compatibility, and simultaneous use of an immunosuppressant. Attention is focused on utilization of somatic stem cells (tissue stem cells, organ stem cells) as autologous cells with no risk of immunologicals rejection. Accordingly, a method of separating mesenchymal stem cells from mammals (see patent document 1), a method of culturing the same (see patent document 2), and novel somatic stem cells (see patent document 3) have also been applied for patent.
Somatic stem cells are differentiated in such a predetermined direction that they are changed into tissue cells in which they occur, and thus it is considered difficult for somatic stem cells to regenerate tissues from which they cannot be collected, but it was nevertheless found that many somatic stem cells have the property of cellular differentiation which is different from their original differentiation. Such property is called the plasticity of somatic stem cells. For example, it came to be known that hematopoietic stem cells can be differentiated not only into blood cells but into any cells such as hepatocytes, skeletal muscle cells, neurons or the like. An approach to new regeneration medicine utilizing such property of somatic stem cells has been developed.
However, the regeneration of tissues or organs cannot be realized by merely administering such stem cells into the living body. For differentiation and growth of cells, the interaction of the cells with their ambient surroundings is very important, and the technology of constructing ambient surroundings suitable for stem cells administered (biomedical tissue technology) is necessary, so there still remain many problems for an approach to regeneration medicine. For example, a method of repairing tissues by introducing a temperature-dependent polymer gel composition containing adenosine phosphate and the like into the cartilages and other tissues in order to support cell proliferation for repairing and regenerating the tissues has also been applied for patent (see patent document 4).
With respect to the plasticity of somatic stem cells, there are two theories, one of which propounds that the plasticity is attributable to transdifferentiation and the other of which propounds that the plasticity is attributable to cell fusion. For example, Alvarez-dolado et al. showed that bone marrow-derived cells (BMDCs) are naturally fused in vitro with neuronal precursor cells, and reported that by bone-marrow transplant, BMDCs are fused in vivo with hepatocytes, brain Purkinje cells and myocardial cells to form fused multinuclear cells (see non-patent document 1). Vassilopoulos et al. reported that upon transplantation of bone marrow hematopoietic stemcells into the liver, the hematopoietic stemcells are fused with hepatocytes to regenerate the liver (see non-patent document 2). It is also reported that after hematopoietic stem cells were transplanted in the heart, the stemcells were not recognized to be transdifferentiated into myocardial cells in genetic study with a mouse having a reporter gene as a gene expressed specifically in myocardial cells (see non-patent document 3). The mechanism of the plasticity of somatic stem cells is examined from every viewpoint but is still not completely elucidated.
Although the mechanism of the plasticity of somatic stem cells is not elucidated, there is a revealed possibility of new therapeutic techniques utilizing somatic stem cell plasticity wherein somatic stem cells are fused with cells of an organ or tissue thereby restructuring a damaged area without causing any immunological rejection.
Heart failure is a life-threatening severe disorder. In heart failure resulting from partial necrosis of heart muscle, even if the heart failure is recovered, the heart muscle once necrotized cannot recover and the patient is at risk of recurrence. Particularly, patients with dilated cardiomyopathy having bad prognosis are increasing, but no established therapeutic method therefor is found. Cardiac transplantation is a prosperous therapy, but owing to shortage of donors, there is a limit to treatment.
Myocardial cells, soon after birth, become adult myocardial cells not having proliferating ability. The heart muscle, when necrotized by myocardial infarction or the like to form fiber tissue partially, will not be reproduced again. The heart muscle having fiber tissue formed becomes thinner, to fail to maintain the pumping ability of the heart, thus making maintenance of heart function difficult.
In recent years, it is attempted to regenerate heart function by transplanting cells directly into the heart with deterioration of heart function. As cells used in transplantation, it is reported to use the following cells: embryonic myocardial cells (see non-patent documents 4 and 5), skeletal muscle blast cells that are skeletal muscle progenitor cells (see non-patent documents 6 and 7), and bone marrow cells exposed to a demethylating agent 5-azacytidine (see non-patent document 8). In any of these reports, animal models are used, and clinical applications are also conducted. For example, Hamano et al. transplanted autologous bone marrow cells into 5 patients with ischemic heart disease. As a result, they has reported that amelioration of ischemic heart disease are recognized in 3 of 5 patients (see non-patent document 9). Strauer et al. injected autologous bone marrow cells by catheter into a site of cardiac infarction of patients with acute cardiac infarction. As a result, they has reported that after 3 months, shrinkage of the site of infarction and amelioration of heart function are recognized (see non-patent document 10).
Although the mechanism for amelioration of heat function by cell transplantation is unrevealed, the amelioration is estimated to be attributable to cell fusion from the above-mentioned genetic examination reporting that there was no recognized transdifferentiation into myocardial cells (see non-patent document 3). In myocardial cells and skeletal muscle cells, multinuclear cells are present, and in skeletal muscle cells, a large number of nuclei are present at the periphery of the cells, and in myocardial cells, 1 or 2 to 3 nuclei are present in the center of the cell.
Cell fusion is a technique used widely in production of antibody and the like, and in addition to viruses such as Sendai virus, compounds such as polyethylene glycol is used as compounds for inducing cell fusion. However, such cell fusion techniques are intended for in vitro use, and these cell fusion promoters when applied to in vivo regeneration medicine may cause fusion of organ cells other than the objective cells, which makes application to clinical medicine substantially very difficult. In restructure of a damaged site of an organ or tissue by cell fusion with stem cells, no chemical is known at present for promoting cell fusion of the organ or tissue with stem cells.    [Patent Document 1] Japanese Patent Application Laid-open (JP-A) No. 2003-052365    [Patent Document 2] JP-A No. 2003-052360    [Patent Document 3] JP-A No. 2004-024246    [Patent Document 4] JP-A No. 2004-501682    [Non-Patent Document 1] Alvarez-dolado, M., et al., Nature, 425, 968-973 (2003)    [Non-Patent Document 2] Vassilopoulos, G., et al., Nature, 422, 901-904 (2003)    [Non-Patent Document 3] Murry, C. E., et al., Nature, 428, 664-668 (2004)    [Non-Patent Document 4] Leor, J., et al., Circulation, 94, II332-II336 (1996)    [Non-Patent Document 5] Li, R. K., et al., Ann. Thorac. Surg., 62, 654-661 (1996)    [Non-Patent Document 6] Murry, C. E., et al., J. Clin. Invest., 98, 2512-2523 (1996)    [Non-Patent Document 7] Scorsin, M., et al., J. Thorac. Cardiovasc. Surg., 119, 1169-1175 (2000)    [Non-Patent Document 8] Tomita, S., et al., J. Thorac. Cardiovasc. Surg., 123, 1132-1140 (2002)    [Non-Patent Document 9] Hamano, K., et al., Jpn. Circ. J., 65, 845-847 (2001)    [Non-Patent Document 10] Strauer, B. E., et al., Circulation, 106, 1913-1918 (2002)